Belta4-3, 11, 16, 20-tetraketo-pregnene and processes of preparing the same



United States Patent ,7

A-3,11,16,20-TETRAKETO-PREGNENE AND PROC- ESSES 0F PREPARING THE SAME Glen E. Arth, Cranford, George I. Poos, North Plainfield, and Lewis H. Sarett, Princeton, N. J., assignors to Merck & Co., Inc., Rahway, N. J., a corporation of New Jersey No Drawing. Original application September 17 1952 Serial No. 310,133. Divided and this application April 8, 1955, Serial No. 500,272

2 Claims. (Cl. 260-397.3)

This invention is concerned generally with dimethylcyclopentanopolyhydrophenanthrene compounds and with processes for preparing them. More particularly, it relates to a novel process for preparing A -3,11,2O- triketopregnene starting with l-alkoxyethinyl-l-hydroxy-Z-methallyl-2,4b-dimethy1 4 keto-l,2,3,4,4a,4b,5,6,7,8,10,10a-

dodecahydrophenanthrene compounds haw'ng in the 7- position a ketal or other substituent convertible to keto by hydrolysis, to the individual steps in this process, and 4 to the intermediate compounds thus obtained.

This application is a division of our co-pending application Serial No. 310,133, filed September 17, 1952.

The A -3,l1,20-triketo-pregnene, which is valuable as an intermediate in the preparation of steroid hormones such as cortisone, may be chemically represented as follows:

as starting material in our novel cally represented as follows:

wherein R is alkyl, and X may be Y,o o

Y1 and Y2 being hydrocarbon radicals, and Z being alkylene. in preparingA -3,11,20-triketo-pregnene, the keto group in ring A is blocked with a ketal or cyclic ketal protecting group. At any stage in the process, this keto group may process, may be; chemi- In each of the process operations utilizedby. us-'-- 2,791,591 Patented May 7, 1957 ICC be regenerated by acid hydrolysis whereby the ketal or cyclic ketalgnouping is hydrolyzed and, at the same time, the double bond shifts from ring B to ring A thus forming an n p-unsaturated ketone. We ordinarily prefer to utilize an ethylenedioxy substituent as the protecting group, and our preferred starting material is therefore l-alkoxyethinyl-l-hydroxy 2 methallyl-2,4b-dimethyl-4- keto 7 ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,IOa-dodecahydrophenanthrene.

Utilizing the latter compound as starting material, and in accordance with our presently invented process, 1- alkoxyethinyl-l-hydroxy 2 methallyl-2,4b-dimethyl-4- keto 7 ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene (Compound 1 hereinbelow) is reacted with a dilute aqueous mineral acid solution to produce the corresponding 1-carboalkoxymethylene-2-methallyl-2,4b-dimethyl 4 keto-7-ethylenedioxy-1,2,3,4,4a,- 4b,5,6,7,8,10,IOa-dodecahydrophenanthrene (Compound 2); the latter compound is reacted with an alkaline saponifying agent thereby forming l-carboxymethylene-2-meth- 4b,5,6,7,8,10,IOa-dodecahydrophenanthrene (Compound 3). The 1-carboxymethylene-Z-methallyl-2,4b-dimethyl- .4-keto 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-

dodecahydrophenanthrene is then reacted with an allcali metal in a lower alkanol or in liquid ammonia to produce 1-carboxymethyl-2-methallyl-2,4b-dimethyl 4 hydroxymetal borohydride'or alkalinet'earth metal borohydride 4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene to form the corresponding 1-carboxymethylene-2-methallyl- 2,4b-dimethyl 4 hydroxy-7-ethylenedioxy-1,2,3,4,- (Compound 5); the latter compound is reacted with an alkali metal in a lower alkanol or in liquid ammonia to produce 1-carboxymethyl-2-metha1lyl-2,4b-dimethyl 4 hydroxy- 7-cthylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene (Compound 4). This compound is reacted with an esterifying agent, preferably an alkyl iodide in the presence of a base and/ or a diazoalkane to produce the corresponding l-carboalkoxymethyl-2-methallyl-2,4bdimethyl-4-hydroxy 7 ethylenedioxy-1,2,3,4,4a,4b,5,6,- 7,8,l0,IOa-dodecahydrophenanthrene (Compound 6). This compound is reacted with an oxidizing agent, preferably under alkaline conditions, thereby forming the corresponding 1-carboalkoxymethyl-2-methallyl-2,4b-di- H methyl-4-keto 7 ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,-

IOa-dodecahydrophenanthrene (Compound 7); alternatively, 1-carboxymethyl-2-methallyl-2,4b-dimethyl-4-hydroxy 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene can be reacted with an oxidizing agent to produce 1-carboxymethyl-Z-methallyl-2,4bdimethyl-4-keto 7 ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,- 10,10a-dodecahydrophenanthrene (Compound 8), which is then reacted with an esterifying agent to form the corresponding 1-carbOaIkoXymethyI-Z-methallyl-2,4b-dimethyl-4-keto 7 ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,l0,-

10a-dodecahydrophenanthrene (Compound 7). The lattercompound is reacted with osmium tetroxide to form the osmate' ester of I-oarboaIkQXymethyI-Z-(beta,gammadihydroxyisobutyl)-2,4b-dimethyl- 4 keto-7-ethylenedi- (Compound 9), which is reacted with an aqueous alcoholic solution of an alkali metal sulfite or bisulfite to produce the caressed;-tearboanoxymahytzi(1m,-

gamma-dihydroxy-isobutyl) 2,4b dimethyl *4 -kcto=7-' compound is reacted, under substantially anhydrous con- *ditions, with a strong "alkali thereby forming A -3 ethyl enedioxy-l1,16,20-triketo-pregnene (Compound 12). The M-B-ethylenedioxy-l1,16,20-triketo-pregnene is reacted with an organic sulfonyl halide thereby forming the corresponding sulfonate ester of A -3-ethylenedioxy- 11,20-diketo-l6-hydroxy pregnadiene (Compound 13), which is reacted with hydrogen in the presence of a hydrogenation catalyst to produce -'A 3 -et hylene"dioxy ILZO-diketO-pre'gnene ('Co'mponrid'll). The-'A -3-ethylenedioxy-1LZO-diketmpregnene"is then reacted with an aqueous mineral acid solution whereupon the-ethylenedioxyisubstituent attached to the 3ecarbon atomz-is'jhydrolyzed and, at the same time, the double bond-shifts from ring B to ring A to form A -3,1l,20vtriketo-pregnene (Compound I The reactions indicated hereinahovemaybechemically represented as follows:

t i om =.OH; en, 70 ii: CH| /"CH,

7 ojcoii dammit =ono OOH doinnound 1 Combound 2 Compound 3 (H15 (ll Ha (J H: (iJ=CH1 i -CH2 horn CH: CH1 OH: HO HO HO "="ci1'='ooo'H V -cH,oo 0H -omco on Q Coni'pound 5 O t: Compound 4 0 Compound 6 1503: (F CHz I 4 CH2 -CH:COOH -CH:COOR

O Compound 8 0 Compound 7 OHQOH (6H: CH:- 0H (3:0

/CH: /C H:

-CH:CO OR -CH2C O O R 1 10 Compound 11 0 l o 0 e gs, [3O

o- A I Q wherein R and R are alkyl radicals and R" is an organic radical.

Although in the foregoing series of reactions, the substituent in ring A of the polyhydrophenanthrene nucleus is shown as an ethylenedioxy grouping, instead of ethylenedioxy, any ketal or cyclic ketal substituent can be used as the protecting grouping. In place of ketal, an enol- -ether may be used as the protecting group, if desired.

The l-alkoxyethinyl-l-hydroxy 2 methallyl-2,4b-dimethyl-4-keto 7 ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,-

10a-dodecahydrophenanthrene compound, employed as starting material in our novel process, is a new compound which may be prepared according to the following procedure: B-ethoxy-propionaldehyde is reacted with ethyl magnesium bromide to produce 1-ethoxy-3-hydroxy-pentane which is reacted with chromic acid thereby oxidizing the hydroxy substituent to form l-ethoxy-S-keto-pentane; the latter compound is treated with ethyl ortho formate and ethanol in the presence of hydrogen chloride to produce l,3,3-trietlroXy-pentane which, upon reaction with hot potassium bisulfate, is converted to 3-ethoxy-l,3- pentadiene. The 3-ethoxy-l,3-pentadiene is reacted with benzoquinone in accordance with the Diels-Alder condensation procedure to produce 5-methyl-6-ethoxy-l,4,4'a,- 5,8,8a-hexahydronaphthalene-1,4-dione which is then reacted with hydrogen in the presence of Raney nickel catalyst to form 5-methyl-6-ethoxy-1,2,3,4,4a,5,8,8a-octahydronaphthalene-l,4-dione; the latter compound is reacted with lithium aluminum hydride to form the corresponding diol, 5-methyl-6-ethoXy-l,2,3,4,4a,5,8,8a-octahydronaphthalene-1,4-diol which is reacted with a hydrolyzing agent to produce 5-metl1yl-6-keto-perhydronaphthalene- 1,4-di0l. The reactions indicated above are described in detail in a co-pending application of one of the present applicants, Serial No. 216,109, filed March 16, 1951. The S-methyl-6-keto-perhydronaphthalene-1,4-diol is then reacted with N-(S-keto-butyl) -N,N-diethyl-N-methyl-ammonium iodide in the presence of potassium hydroxide to produce 7-keto-4b-methyl-1,2,3,4,4a,4b,5,6,7,9,10,1021- dodecahydrophenanthrene-1,4-diol; this reaction is described in detail in co-pending application, Serial No. 228,126, filed May 24, 1951. The 7-keto-4b-methyl- 1,2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene- 1,4-diol is reacted with ethylene glycol in ethylene dichloride solution and in the presence of p-toluene sulfonic acid catalyst thereby forming l,4-dihydroXy-4b-methyl- 7-ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene. The 1,4-dihydroxy-4b-methyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophe- Compound 15 nanthrene is reacted with cyclohexanone and aluminum isopropoxide in benzene solution to produce the corresponding 1-keto-4-hydroxy-4b-methyl 7 ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene. The reactions indicated hereinabove are described in detail in a co-pending application of the present applicants, Serial No. 286,808, filed May 8, 1952. V v I The 1-keto-4-hydroxy-4b-methyl-7-ethylenedioxy 1,2, 3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene is reacted with methyl iodide in the presence of potassium tertiary butoxide in benzene thereby forming 1-lreto-2,4bdirnethyl-4-hydroxy-7-ethylenedioxy-1,Z,3,4,4a,4b,5,6,7,8, 10,10a-dodecahydrophenanthrene; the latter compound is reacted with chromium trioxide-pyridine complex to form 1,4-diketo-2,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5, 6,7,8, l0,10a-dodecahydrophenanthrene. The methylation reaction indicated hereinabove is described in detail in a co-pending application in which one of the present applicants is co-inventor, Serial No. 306,488, filed August 26, 1952. The oxidation reaction indicated hereinabove is described in detail in a co-pending application in which one of the present applicants is the sole inventor, Serial No. 292,985, filed June 11, 1952. The 1,4-diketo-2,4bdimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10'adodecahydrophenanthrene is reacted with methallyl iodide in a tertiary butyl alcohol solution of aluminum tertiary butylate, thereby forming 1,4-diketo-2-methallyl-2,4b-dimethyl 7 ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene. The latter compound is reacted in ether-benzene solution with an alkoxy acetylene magnesium bromide to produce the corresponding 1-alkoxyethinyl-1-hydroxy-2-meth'allyl-2,4b-dimethyl-4-keto-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,1021 dodecahydrophe nanthrene. The reactions indicated hereinabove are described in detail in two co-pending applications of the present applicants, Serial No. 306,509, filed August 26, 1952, and Serial No. 308,172, filed September 5, 1952. Where it is desired to utilize another enol-ether substituent to protect the 7-keto grouping, this is introduced in the foregoing procedure by reacting the intermediate 1,4-dihydroxy-7-keto-4b-methyl 1,2,3,4,4a, 4b,5,6,7,9,10,l0a-dodecahydrophenanthrene under substantially anhydrous conditions and in the presence of'an 1 acid catalyst, with a lower alkanol such as an excess amount of methanol, ethanol, propanol, butanol, and-the like, or an excess of another low molecular weight glycol such as propylene glycol, butylene glycol, and the like. If it is desired to use an enol-ether as the protecting group, the 1,4-dihydroxy-7-keto-4b-methy1-1,2,3-,4;4a;4b,

cyclic ketal, ketal,

5,6,7,9,10,10a-dodecahydrophenanthrene is reacted, under substantially anhydrous conditions in the presence of an acid catalyst with an alkyl ortho formate.

The rearrangement ofthe l-alkoxyethinyl-1-hydroxy-2- methallyl-2,4b-dimethylt4:1eeto-7-cthylenedioxy-1,2,3,4,4a, 4b,5,6,7,8,10,lOa-dodecahydrophenanthrene is carried out by bringing this compound into intimate contact with an aqueous mineral acid in solution in an organic solvent for the compound, for example a cyclicether such as tetrahydrofuran, tetrahydropyran, dioxaneor an alkanol such as ethanol, ispropanol, butanol and the like, under which conditions the ketal or enol ether substituent attached to the C-7 carbon atom is-not:appreciablyhydrolyzed. We ordinarily utilize tetrahydrofuran as the organic solvent in conjunction with aqueous sulfuric acid'solution, and allow the slightly exothermic reaction which takes place to proceed at a temperature of about 25-30" C. Under these conditions, the reaction is ordinarily complete in about three and one-half hours. In accordance with this procedure, there is obtained-the desired l-carboalkoxymethylene-Z-methallyl 2,4b-dimethyl-4-keto-7-ethylenedioxy-1,2,3,4,4a,4b,5;6,7,8,10,102. dodecahydrophenanthrene admixed with a by-product, l-carboalkoxymethyl-l-hydroxy 2 methyl-2,4b-dimethyl-4-keto-7-ethylenedioxy-l ,2,3,4,4a,4b,5,6,7,8, 10, 1,021;- dodecahydrophenanthrene. These two products can be conveniently isolatedfrom thereaction mixture byqneutralizing the mineraLaeidwith a mildly aqueous alkaline solution, preferably a' saturated aqueous solutionofsodium bicarbonate, distilling the organic solvent underreduced; pressure, and extractingthe oil which separatesduring distillation into the ether. After washing, drying and evaporating the ether extract, there is obtained a residual oily material from which itis possible to fractionally crystallize the foregoing components in substantially pure form. It is ordinarilypreferred; however, to separate these two prod-v ucts inpure form by chromatography on acid-washed alumina. This. is accomplished by dissolving the residual oily material in benzene-petroleum'ether, contacting tbis solution with acid washed'altunina and eluting the adsorbatewith a mixture ofpetroleum.ether-ether. From the eluates, richer in the petroleum ether component is obtained the 1-carboalkoxyrnethylene-2-methallyl-2,4b-dimethyl-,4-keto 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,l0, 10a-dodecahydrophenanthrene and from the following fractions whichcontain a relatively higher proportion. of ether is obtained; the ,l-carboalkoxymethyl-l-hydroxy-Z- methallyl-,2 ,4b-dir nethyl-4:ketoJ-ethylenedioxy-l,2,3,4,4a, 4b,5',6,7,8,10;10a-dodecahydrophenanthrene.

The saponificationof the ,estergrouping in the l-carboalkpxynlethyleneirmethailyl 2,4b-dimethyl-4-keto7-ethyleuedioxy'l,2,3,4,4a,4b,5,6,7,8,10,108. dodccahydrophenanthrene is conducted; utilizing an alkaline hydrolyzing agent since the 7.-position substituent is unstable under the conditions normally encountered in the acid hydrolysis ofv esters. The hydrolysis-is conveniently carried out utilizing; an aqueous methanolic solution containing potassium carbonate and a small amount: of potassium hydroxide, but other alkaline hydrolyzing agents can be utilized if desired. When this preferred hydrolyzing agent is utilized, saponification may be carriedout at room temperature, or more rapidly, if desired, by heating the reactants at thev refluxtemperature of the solution. The methanol is evaporated under reduced pressure, and the aqueous mixture diluted with approximately an equal volume of water, whereupon the potassium salt of Z-carboxymethylene-Z-methallyl-ZAb dirnethyl-4:keto-7-ethylenedioxyl ,2, 3,4,4a,4b,5,6,7,8,1 0,10a dodepahydrophenanthrene may precipitate-as an oil. The-aqueous solution or suspension is then extracted with etherand the aqueous mixture is acidified with. a mildlyacidic reagent such as sodiumdihydrogen phosphate, The acidic material which separates is extracted with chloroform, the chloroform extracts are driedand evaporated under, reduced pressure; to give 1- o rme hy ene =m h 1 l: rd m t y e tnfl borohydride or an alkaline earth metal borohydride such ethyl acetate. As set forth hereinabove, the l-carboxyruethylene-2- methallyl 2,4b dimethyl 4 keto 7 ethylenedioxyl,2;-3',4,4a, 4b, 5, 6, 7, 8, 10,10a dodecahydrophenanthrene can be converted directly to l-carboxymethyl-Z- methallyl- 2,4b dimethyl 4 hydroxy 7 ethylenedioxy l,2,3;4,4a,4b,5,6,7,8,10,10a dodecahydrophenam threne by reaction with an alkali metal, such as sodium, lithium, or potassium, or this reaction can be carried out in two operations, first reducing the 4-keto substituent to hydroxy utilizing an alkali metal borohydride such as sodium borohydride, lithium borohydride, potassium as calcium borohydride, and then reducing the l-carboxymethylene substituent utilizing the alkali metal.

Thereaction between the 1-carboxymethylene-Z-methallyl 2,4b' dimethyl 4 keto 7 ethylenedioxy 1,2,- 3,4a-,4b,5;6,7,8,l0,10a dodecahydrophenanthrcne and the alkalimetah borohydride or alkaline earth metal borohydride is conducted by suspending the hydrophenanthrene compound in water or in aqueous organic solvent such as aqueous tetrahydrofuran, aqueous dioxane, aqueous alkanols, and the like, and adding the alkali metal or alkaline earth metal borohydride cautiously to the mixture. After all the reducing agent has dissolved, the resulting mixture is allowed to stand preferably at a temperature between about room temperature and C., althoughhigher andlower temperaturesmay be used if desired. When the. reaction is carried out. at a tem peratureof. about 30 C., the reaction is ordinarily complete after a reaction time of about 24 hours. The aqueous mixture is carefully acidified, preferably maintaining the pH aboveabout. 3.5; it is preferred to.utilize sodium dihydrogen phosphate for. this acidification. The product which precipitates is extracted with an organic solvent.

such as chloroform. Thechloroform extracts are washed, dried and evaporated invacuo to give an oil which can becrystallized from ether to give crystalline l-carboxymethylene- 2 methallyl 2,4b dimethyl 4 hydroxy- 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene.

The latter product or, if desired, the starting l-carboxymethylene 2 methallyl 2,4b dimethyl 4 kcto 7- ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene is reacted with an alkali metal such as metallic lithium, sodium or potassium, and the like, in solution in a. lower alkanol and/ or in liquid ammonia.

Where metallic lithium or potassium are used as thereducingagents, it is preferred to use liquid. ammonia. The reaction system which has been found most advantageous is potassium-liquid ammonia-isopropanol. The reaction between the 1 carboxymethylene- 2 methallyl- 2,4b dimethyl 4 (keto or hydroxy) 7 ethylenedioxy l,2,3,4,4a,5',6,7,8,10,10a dodecahydrophenanthrene and metallic lithium or potassium is conveniently carried out by suspending the hydrophenanthrene compound in. liquid ammonia and adding the alkali metal portionwise to the suspension. If desired, a lower alkanol such as ethanol, butanol, and the like may be added to the reaction mixture; although the reduction reaction will occur in the. absence of the alkanol, the yield of the desired product is improved, in some cases, by the use of the. alkanol. The liquid ammonia reaction mixture is stirred at the boiling point of liquid ammonia until the ammonia has evaporated. The crude reaction mixture is treated with benzene, and, if necessary, a small amount of ethyl acetate or alcohol is added to destroy the excess alkalirnetal, The resulting mixture isthen diluted with water, thebenzene layer is-discarded, and-the alkaline layer containingthereduction product is acidified. The material whichprecipitates is extracted with chloroform, andthechlorofornlcxtract is washed, dried and evaporated. The oily material thus obtained is crystallized by heating with ether to give crude 1-carboxymethyl-2- methallyl 2,415 dimethyl 4 hydroxy 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene.

When sodium or potassium is used as the reducing agent, the reaction is conveniently carried out by bringing together the 1-carboxymethylene-2-methallyl-2,4bdimethyl 4 (keto or hydroxy) 7 ethylenedioxyl,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene, alkali metal, and a hot lower alkanol, and stirring the resulting mixture under reflux for a period of about fifteen minutes. The reaction mixture is evaporated to about one-half volume in vacuo, diluted with water and the aqueous solution is carefully acidified. The acidic aqueous mixture is extracted with chloroform, and the chloroform extract is dried and evaporated in vacuo. The residual material consists of crude l-carboxymethyl- 2 methallyl 2,4b dimethyl 4 hydroxy 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,l0,la dodecahydrophenanthrene.

When the reduction is carried out utilizing as starting material the 1 carboxymethylene 2 methallyl 2,4bdimethyl 4 keto 7 ethylenedioxy 1,2,3,4,4a,4b, 5,- 6,7,8,10,10a-dodecahydrophenanthrene, there may be obtained, in addition to the 1-carboxymethyl-Z-methallyl- 2,4b dimethyl 4 hydroxy 7 ethylenedioxy 1,2,3,- 4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene, a small amount of 1 carboxymethyl 2 methallyl 2,4b dimethyl 4 keto 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,- 7,8, 10, 1 Oa-dodecahydrophenanthrene.

Esterification of the 1-carboxymethyl-2,4b-dimethyl-4- (hydroxy or keto)-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,- l0,10a-dodecahydrophenanthrene can be carried out by any of the usual methods of esterification but, in view of the ease of hydrolysis of the ketal substituent in the 7-position, it is ordinarily preferred to conduct this esterification under alkaline conditions using a diazoalkane or an alkyl iodide in the presence of a base as the esterifying agent. The reaction utilizing a diazoalkane such as diazomethane or diazoethane is conveniently carried out by dissolving the 1-carboxymethyl-2-methallyl-2,4b-dimethyl-4-(hydroxy or keto)-7-ethylenedioxy-l,2,3,4,4a,- 4b,5,6,7,8,l0,lOa-dodecahydrophenanthrene in an organic solvent such as ether and adding to this solution an excess of the diazoalkane in an inert organic solvent medium such as ether. The resulting solution is allowed to stand at approximately room temperature until the evolution of nitrogen ceases, the solvents are evaporated, and the residual oil is crystallized -'to give l-carboalkoxymethyl 2 methallyl 2,4b dimethyl 4 (hydroxy or keto) 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8;l0,10adodecahydrophenanthrene.

The 1-carboalkoxymethyl-2-methallyl-2,4b-dimethyl-4- hydroxy 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,l0,- lOa-dodecahydrophenanthrene can be converted by reaction with an oxidizing agent to the corresponding 4- keto derivative, which is alternatively obtained by the esterification of the l-carboalkoxymethyl-2-rnethallyl- 2,4b dimethyl 4 keto 7 ethylenedioxy-l,2,3,4,4a,- 4b,5,6,7,8,10,10a-dodecahydrophenanthrene as described hereinabove. As oxidizing agent for this reaction, we ordinarily prefer to utilize chromium trioxide-pyridine complex, although other oxidizing agents such as chromic acid may be employed if desired. Using the preferred oxidant, the 1-carboalkoxymethyl-Z-methallyl-2,4b-dimethyl 4 hydroxy 7 ethylenedioxy 1,2,3,4,4a,4b,- 5,6,7,8,10,10a-dodecahydrophenanthrene is dissolved in pyridine and mixed with the complex formed by adding chromium trioxide to an excess of pyridine. The resulting mixture is allowed to stand at a temperature within the range of about 0 C. to 100 C. for a period of time, depending upon the temperature; at room temperature, the reaction is ordinarily complete in about hours. The reaction mixture is diluted with water and the aqueous solution is extracted with a water-immiscible organic solvent such as ether. The organic solvent extracts are Washed with water, dried, and the solvent evaporated. The residual oil is crystallized to give l-carboalkoxymethyl 2 methallyl 2,4b dimethyl 4 keto 7 ethylenedioxy .1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene.

Further oxidation of the latter compound converts the methylene substituent in the methallyl radical to a keto grouping. This can be accomplished in a two-step oxidation utilizing osmium tetroxide followed by periodic acid or in a single-step utilizing ozone. Where the osmium tetroxide procedure is used, the l-carboalkoxymethyl 2 methallyl 2,4b dimethyl 4 keto 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene is dissolved in a dry ether-benzene solution and approximately one equivalent of osmium tetroxide is added to the solution. In a few minutes the osmate ester of the 1-carboalkoxymethyl-2- 3, -dihydroxy isobutyl) 2,4b dimethyl 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene precipitates, and the resulting mixture is allowed to stand at about room temperature for a period of about one:

hour. At the end of this period, the reaction is substan-- tially complete. An organic solvent for the osmate ester, for example a lower alkanol such as ethanol, or a cyclicether such as tetrahydrofurane is added to the reaction mixture to dissolve the osmate ester, and the latter is reacted with a mildly alkaline hydrolyzing agent under reducing conditions such as an aqueous solution of an alkali metal sulfite or bisulfite. The osmium oxide which precipitates from the hydrolysis is removed by filtration,

and the filtered solution is evaporated under reduced pressure. The residual oily material thus obtained is shaken with a mixture of ether and water, the ethereal extract is washed with water, dried and evaporated to give crystalline l-carboalkoxymethyl 2 (5, dihydroxyisobutyl) 2,4b dimethyl 4 keto 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a, dodecahydrophenanthrene.

The 1 carboalkoxymethyl-2- (fi,'y-di'hydroxyisobutyl)- 2,4b dimethyl 4 keto 7 ethylenedioxy l,2,3,4,- 4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene solved in an organic solvent for the compound for example a lower alkanol, such as ethanol, and a cyclic ether, such as tetrahydrofuran and the like, and to this solution are added pyridine and an aqueous solution of periodic acid. The glycol cleavage which takes place is ordinarily complete in a few minutes. The reaction mixture is diluted with water, and the aqueous reaction mixture is extracted with an organic solvent such as ether. The organic solvent'extract is washed, dried, and evaporated to give an oily product which can be crystallized to give substantially pure 1-carboalkoxymethyl-2-acetonyl-2,4bdimethyl 4 keto 7 ethylenedioxy 1,2,3,4,4a,4b,5,- 6,7,8,10,10a-dodecahydrophenanthrene.

When the conversion of the Z-methallyl substituent to an acetonyl radical is conducted utilizing ozone instead of osmium tetroxide followed by periodic acid, the 1- carboalkoxymethyl 2 methallyl 2,4b dimethyl 4 keto 7 ethylenedioxyl 1,2,3,4,4a,4b,5,6,7,8,10,10a dodeca'hydrophenanthrene is dissolved in a lower alkanol such as methanol, the solution is cooled to a low temperature of about C., and ozonized oxygen containing one equivalent of ozone based on the hydrophenanthrene compound is passed through the solution. The resulting mixture is warmed to approximately 0 C., and the ozonide product in the reaction mixture is decomposed under reductive conditions either by means of a;

small amount of zinc and aqueous acetic acid, or catalytically by contacting the ozonide in an aqueous me dium with hydrogenand a platinum catalyst. When the ozonide is reacted with zinc and aqueous acetic acid,

the reaction mixture is made slightly alkaline, filtered and the solvents evaporated therefrom in vacuo at is dis- Y about twelve to twenty-four hours. 7

sulfony-l chloride and pyridine are neutralized bythe ad.

temperaturebelow; about -20* C; The residual material is extracted with ether,- the ethereal solution is. chromatographed on acid-washedalumina and'the alumina-am sorbate iseluted utilizing ether-petroleum ether. Upon evaporation of the ether-petroleum ether eluate, .there is obtained 1-carboalkoxymethyl-Zacetonyl-2,4brdimethylketo 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,'7,8,'10,109. dodecahydrophenanthrene.

We then prcparea substantially anhydrous solution of 1-- carboalkox-ymethyl 2" acetonyl 2,4bdimethyl 4 keto 7 ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene in an aromatic. hydrocarbon such as benzene, toluene, andthe like. This solution is brought into Contact with a solid, anhydrous, strongly basic material, for example analkali metal alkoxide, such as sodium methoxide, potassium t-butoxide, an al-' kali metahsuch as metallic sodium, an alkali metal hy dride,- such as sodium hydride, an. alkali metal amide such as soda'mide, and the like. The resulting mixture is ordinarily stirred at -a temperature Within therange of about-20 to 50 0. although temperatures somewhat belowor above this range maybe used, if desired. When.

the reaction is carried out at about room temperature, the cycliz-ation is substantially complete in approximately ten hours; The reaction mixture is poured into water and immediately acidified with van excess of a mildly acidic reagent such as an aqueous solution of primary sodium phosphate. The acidified solution is extracted with" an organic solvent such-as chloroform and the solvent extract dried, filtered and evaporated to give crystalline A -3-ethylenedioxy-1 l,l6,20-triketo-pregnene, which can be further purified if desired by recrystallization. Acid hydrolysis of the A 3 ethylenedioxy-l1,16,20-triketopregnene gives A -3,11;16,2O-tetraketo-pregr ene.

The A -3-ethylenedioxy-11,16,20-triketo-pregnene is then reacted with an organic sulfonyl chloride, preferablyp-toluene sulfonyl chloride. This reactionfis carried out dissolving the pregnene compound in a tertiary amine such as pyridine and adding the organic sulfonyl chloride to theresulting solution. The reactionis allowed to proceed at about room, temperature under which conditions the reaction is ordinarily complete in The excess organic dition of a mildlyalkaline aqueous solution such as aqueous sodium bicarbonate,- and "the resulting mixture is agitated for a short period of-time, during which time An organic-solvent" such as the sulfonale crystallizes; benzene is. added to-the reaction mixture, the mixture'is poured into ice water, and the organic layer is separated: The organic layer is washed with water, dried and evap- The residual material-canbe purified orated in vacuo. by recrystallization to give the- 16-sulfonate ester of A -3-ethylenedioxy 16 hydroxy-l1,20-diketo-pregnadiene in substantially pure form.

The catalytic hydrogenation. of. the latter material-is conveniently carried out by dissolving the-.16-sulfonateester of A -3-ethylenedioxy 16 hydroxy-11,20-.diketopreguadiene in benzene, adding a hydrogenation. catalyst, such as palladiumon bariumcarbonate -and contacting the mixture with-hydrogen at atmospheric, pressure, or preferably atsuperatmospheric pressure. Whenfihe ydrogenationreaction is carried out atroomtemperature and at a pressure ofabout forty pounds persquare inch, the reaction is substantially complete in about twenty hours. amounts ofcatalyst during the course .ofthehydrogenation. The hydrogenation mixture is filtered, and the filtered solution is evaporated in vacuo. The. residual oil is crystallized to give substantially pure .A -3-ethylenedioxy-l 1,20-diketo-pregnene.

The latter compound. is treated with a .hydrolyzing agent, preferably an aqueous mineral acid such as hydro chloric acid, perchloric acid, p-tol uene sulfonic acid, and thelilre, thereby hydrolyzing the ketal substituent in the it is ordinarily preferred 'to. add additional;

3-'position-of the molecule. When aqueous perchloric acid is employed, the hydrolysis is, conveniently carried out by dissolving the di-il-ethylenedioxy-l1,2;0 diketopregnene in an organic solvent suchas tetrahydr'ofuran, addinga dilute aqueous solutionrof perchloric acid to the resulting solution, and allowingthe resultingmixture to stand at about room temperature for a period of about three to four hours. The solvents are evaporated in vacuo, and the residual material is extracted with an organic solvent such as chloroform. The chloroform extract is dried, the chloroform evaporated in vacuo, and the residual material is crystallized to give substantially pure A -3,1 1,20-triketo-pregnene.

The stereoisomeric. form of A -3,'l1,20-triketo-pregnenc having a melting point of about 175-176 C. possesses the stereoisorneric configuration characteristic of thenaturally-occurring steroid hormonessuch as progesterone. We refer to this stereoisomer by thelname of 11- keto progesterone. form of a racemic mixture of the dand l-forms, and is referred to more specifically as dl-l l-keto progesterone.

The 3-ethylenedioxy derivative of dl A -3,l1,20-1triketopregnene of melting point 175476 C. obtained as hereinabove describedmay be converted to the therapeutically active material 3,11,20-triketo-17a-hydroxy-2l-acetoxy- -pregnene as follows: dl-3-ethylenedioxy-ll,20 diketo- M-pregnene is treated with dirnethyl oxalateand then with alkali to form the C-2l oxalyl acid derivative. On formation of the strychnine salts of the components of this racemic mixture the d-salt precipitates and may be recovered by filtration. Decomposition-of thisstrychnine salt and hydrolysis of the C21 oxalyl acid group yields 3-ethylenedioxy-lLZO-diketo-M-pregnene identical with that obtained from naturally occurring materials.

Iodination under alkaline conditions. of .the natural isomer of the Zl-oxalyl acid 'of 3-ethylenedioxy-1l,20- diketo-u -pregnene, whichmay be obtained in the above described resolution procedure, yields 3-ethylcnedioxyll,20-dileto2l-iodo-d -pregnene. By treatment of this latter compound with'potassium acetatethere is obtained 3-ethylenedioxy 11,20-diketo-2l-acetoxy-M-pregnene.. of melting point 193.5494 C.

Reaction of the last mentioned compound witlrhydrogen cyanide followed by dehydration of the C-20 cyanhydrin thus formed with phosphorous oxychloride yields 3-ethylenedioxy-l1-keto2t)-cyano-2l-acetoxy Ma -pregnadiene, which may be oxidized with potassium permanganate to 3-ethylenedioxy-l l,20-diketo-l7a-hydroxy- 2l-acetoxy-A -pregnenc. 3,1 l,ZO-triketod7ot-hydroxy 2 lacetoxy-Al-pregnene, alternatively known as cortisone acetate, may. be preparcdby acid hydrolysis of the. above mentioned 3-ethylenedioxy-11,20-diketo-l7bt-hydroxy-21- acetoxy-A -pregnene.

The 3-ethylenedioxy derivative of dl-3,l1,20triketon' -pregnenc may also be converted into dl-3,1l,20-triketo-17u-hydroxy-2l-acetoxy-A -pregnene by the procedure herciuabove described.

The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given primarily by way of illustration and notof limitation.

Example -1 to the reaction mixture, and the. ,tetrahydrofuran was.

evaporated from the aqueous. mixture under reduced pressure. The oil which separated was extracted into.,.cther; the ether extract was washed once with water, dried over This compound is obtained in thesodium sulfate, and the ether was evaporated. The residual oil material was dissolved in ether and chromatographed on acid-washed alumina. The adsorbate was eluted with mixtures of ether and petroleum ether; upon evaporation of the 8:2 petroleum ether-ether eluate there was obtained 1-carboethoxymethylene-2-methallyl-2,4bdimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene 4 one; upon evaporation of the 7:3 petroleum ether-ether eluate there was obtained 1 carboethoxymethyl 2 methallyl-2,4b dimethyl-7- ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-1-ol-4-one having an M. P. of 99-101 C.

In accordance with the foregoing experimental procedure and utilizing as starting material the stereoisomer of l ethoxyethinyl 2 methallyl 2,4b dimethyl 7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 1 ol 4 one having an M. P. of 133-- 134 C., there was obtained the stereoisomer of 1 carboethoxymethyl 2 methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 1 o1 4 one having an M. P. of 9910l C. and the stereoisomer of l-carboethoxymethylene-2 methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4, 4a, 4b, 5,6,7,8,l0,la'- dodecahydrophenanthrene 4- one having an M. Prof l33-l34 C. and l51l52 C. (dimorphic).

By using a stereochemical modification of the above 1'- ethoxyethinyl 2 methallyl 2,4b dimethyl 7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene 1 ol 4 one starting material having an M. P. of 131-132 C. there was obtained the stereoisomer of 1 carboethoxymethyl 2 methallyl- 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6, 7,8,10,10a-dodecahydrophenanthrene-l-ol-4-one having an M. P. of 146 C. and the stereoisomer of l-carboethoxymethylene 2 methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one having an M. P. of 94-96 C.

Example 2 A suspension of 4.1 g. of l-carboethoxymethylene-Z- methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4, 4a,5,6,7,8,10,10a dodecahydrophenanthrene 4 one in 50 ml. of methanol and 50 ml. of water containing 10 g. of potassium carbonate and l g. of potassium hydroxide was heated to boiling under reflux for a period of two and one-half hours. At the end of this time, all of the ester had dissolved. The methanol was evaporated under reduced pressure, whereupon the potassium salt of 1 carboxymethylene 2 methallyl 2,4b dimethyl- 7 ethylenedioxy 1,2,3,4,4a,4-b,5,6,7,8,l0,10a dodecahydrophenanthrene 4 one separated as an oil, and approximately 50 ml. of water was added to dissolve the salt. The aqueous mixture was extracted once with ether, and then acidified with excess sodium dihydrogen phosphate. The acidified mixture was then extracted with chloroform, and the chloroform extract was dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure at a bath temperature which did not exceed about 40 C. The residual crystalline ma terial was washed with ether and recrystallized from ethyl acetate to give substantially pure l-carboxymethylene- 2 methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3, 4,4a,4b,5,6,7,8,10,IOa-dodecahydrophenanthrene 4 one.

In accordance with the foregoing experimental procedure and utilizing as starting material the stereoisomer of l carboethoxymethylene 2 methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,l0,l0adodecahydrophenanthrene-4-one having an M. P. of 133- 134 C.; 151.2 C., there was obtained the stereoisomer of l carboxymethylene 2 methallyl 2,4b dimethyl- 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 one having an M. P. of 223- 225 C.

When the stereoisomer of 1-carboethoxymethylene-2- methallyl 2,4b dimethyl 7 ethylenedioxy l,2,3,4; 4a,4b,5,6,7,8,10,l0a dodecahydrophenanthrene 4 one having an M. P. of .94-96" C. was used as starting material and the saponification conducted as described in the first paragraph of the present example except that the potassium hydroxide was omitted from the saponification mixture, there was obtained the stereoisomer of 1-car-' boxymethylene 2 methallyl 2,4b dimethyl 7 ethyleuedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydro= phenanthrene-4-one havingan M. P. of 203-205 C.

A solution containing about 50 mg. of l-carboxymeth ylene 2 methallyl 2,4b dimethyl 7 ethylenedioxy- 1,2,3,4,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4- one and about 15 mg. of p-toluene sulfonic acid in about 3 ml. of acetone was heated under reflux for a period of approximately twenty minutes. The acetone reaction mixture was diluted with water and the resulting aqueous mixture was extracted with chloroform. The chloroform extract was dried and evaporated to dryness to give l-carboxymethylene 2 methallyl 2,4b dimethyl l,2,3,4, 4a,4b,5,6,7,9,l0,10a dodecahydrophenanthrene 4,7- dione.

Example 3 A solution of 100mg. of 1-carboxymethylene-2-methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a, 4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 one was suspended in 5 ml. of water. One gram of sodium borohydride was added cautiously until the initial reac-- tion Was completed. After all of the reducing agent had 1 dissolved, the mixture was heated at 100 C. for three hours. The reaction mixture was cooled, acidified with sodium dihydrogen phosphate, and the acidified mixture extracted with chloroform. The chloroform extract was washed with water, dried over anhydrous sodium sulfate, and filtered, and the chloroform was evaporated from the filtered solution in vacuo at a bath temperature of less than about 40 C. The residual oil was crystallized from ether, and recrystallized from ethyl acetate to give substantially pure 1 carboxymethylene 2 methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a, 4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 01.

In accordance with the foregoing procedure and utilizing as starting material the stereoisomer of 1-carboxy methylene 2 methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 one having an M. P. of 223-225 C. there was obtained the stereoisomer of l-carboxymethylene-Z- methallyl 2,4b dimethyl 7 ethylenedioxy l,2,3,4, 4a,4b,5,6,7,8,l0,l0a dodecahydrophenanthrene 4 01 having an M. P. of 211-214 C.

Upon heating, under reflux, a solution of 50 mg. of lcarboxymethylene-2-methallyl-2,4b-dimethyl 7 ethylenedioxy l,2,3,4',4a,4b,5,6,7,8,10,10a dodecahydrophe nanthrene-4-ol and 15 mg. of p-toluene sulfonic acid in 3 ml. of acetone for a period of about 20 minutes, there is obtained 1-carboxymethylene-2-methallyl-2,4b-dimethyl-l,2,3,4,4a,4b,5,6,7,9,10,10a -dodecahydrophenanthrene- 4-ol-7-one.

Example 4 A suspension of 5 g. of 1-carboxymethylene-Z-methallyl-2,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8, 10,10a-dodecahydrophenanthrene-4-one in 20 ml. of tetrahydrofuran and 200 ml. of liquid ammonia was stirred at a temperature of -40 C. while pea-sized portions of lithium were added at intervals and at a rate sutficient to maintain an excess of the alkali metal. The liquid am monia reaction mixture was stirred at a temperature of about 40 C. for a total time of about two hours during which the addition of the lithium was continued; a total of about 500 mg. of lithium was used. The excess ammonia was evaporated from the reaction mixture at room temperature, about 200 ml. of benzene was added, and ethyl acetate was then added cautiously to destroy the excess lithium. One hundred and fifty milliliters o1 15 water was added to the mixture and the benzene layer was discarded. The alkaline aqueous layer was acidified with excesssodium dihydrogen phosphate and the acidified aqueous mixture extracted with chloroform. The chloroform extract was washed with water, dried over anhydrous sodium sulfate, filtered, and the chloroform evaporated from the filtered solutionunder reduced pressure. The residual oil was covered with 50 ml. of ether and the mixture heated under reflux for about. fifteen minutes. The crystalline precipitate which formed was recovered by coolingthe ethereal mixture and filtering. This crystalline material was fractionally crystallized from acetonitrile to give 1-carboxymethyl-2methally1 2,4bdimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one, which crystallized first, and l-carboxymethyLZ-methallyl-2,4b-dirnethyl 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrenel-ol (the more solublecompound).

In accordance with the foregoing experimental procedure and utilizing as starting material the stereoisomer of l-carboxymethylene-2-methallyl-2,4b'dimethyl 7 ethylenedioxyl,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophcnanthrene-4-one having an M. P. of 223-225 0, there were obtained the stereoisomer-of l-carboxymethyl-Z- methallyl-2,4b-dimethyl-7-ethylenedioxy l,2,3,4,4a,4b,5, 6,7,8,l0,lOa-dodecahydrophenanthrene-4-one having an M. P. of 201-203 C.,and two-stereoisomers of l-carboxymethyl-2-methallyl 2,4b-dimethyl-7-ethylenedioxy 1,2,3, 4,4a,4b,5,6,7,8,l0,la-dodecahydrophenanthrcne-4-o1, one of which has an M. P. of 226228 C. and the other an M. P. of 234-235 C.

When the stereoisomer of 1-carboxymethyl-2-methallyl- 2,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10, a-dodecahydrophenanthrene-4-one having an M. P. of 203-205 C. was used as starting material there were obtained two stereoisomers of 1-carboxymethyl-2-methallyl- 2,4b-dimethyl-7-ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10, 10a-dodecahydrophenanthrenel-o1 one of which has an M. P. of 255257 C. and the other an M. P. of 216- 220 C.

When 1-carboxymethylene-2-methallyl-2,4b-dimethyl- 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol was utilized 'as starting material in the foregoing procedure, the product obtained was l-carboxymethyl-2-methallyl 2,4b-dimethyl-7-ethylenedioxyl,2,13,4,4a,4b,5,6,7,8, 10,10a dodecahydrophena'nthrene- A solution containing about 50 mg. of l-carboxymethyl- 2-methallyl-2,4b dimethyl-7-ethylenedioxy l,2,3,4,4a,

4b,5,6,7,8,10,lOa-dodecahydrophenanthrene 4 oland aboutlS mg. of p-toluene sulfonic acidin about 3 ml. of acetone was heated-under reflux for a period of about twenty minutes. The acetone reaction mixture was diluted with water and the resulting aqueous mixture extracted with chloroform. The chloroform extract was dried and evaporated to dryness to give l-carboxymethyl- Z-methallyl 2,4b dimethyl 1,2,3,4,4a,4b,5,6,7,9,10,10adodecahydrophenanthrene-4-ol-7-one. When the stereoisomer of 1-carboxymethyl-Z-methallyl-2,4b-dimethyl-7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-d0decahydrophenanthrene-4-ol having an M. P.' of 255-257" C. was hydrolyzed in accordance with the foregoing procedure there was obtained the stereoisomer of l-carboxymethyl- 2 methallyl-2,4b-dimethyl 1,2,3,4,4a,4b,5,6,7,9,10,10adodecahydrophenanthrene-4-ol 7-onehaving an M. P. of 215-217 C.; when the stereoisomer of l-carboxymethyl- Z-methallyl-2,4b dimethylr7-ethylenedioxy 1,2,3,4,4a,4b, 5,6,7,8,l0,10a-dodecahydrophenanthrene-4-ol having an M. P. of 216-220' C. was similarly hydrolyzed there was obtained the stereoisomer of l-carboxymethyl-IZ-methallyl- 2,4b-dimethyl l l,2,3,4,4a',4b, 5,6,7,8,lO,l0a-dodecahydrophenanthrene-4-ol-7-one having. an M. P. of 190-192 C.

When 1 carboxymethyl-Z-methallyl-2,4b-dimethyl-7- ethylenedioxy 1,2,3,4,4a,4b',5,6,7,8,l0 ,10a,-dodecahydrophenanthrene-l-one' is similarly hydrolyzed using an ace- '16 tone solutionof p-toluene sulfonic acid, there is obtained 1-carboxymethyl-2 methally-2,4b dimethyl l,2,3,4,4a, 4b,5,6,7,9,10,10a-dodecahydrophenanthrene-4,7-dione.

Example 5 One and two-tenths gram of sodium metal was added to 20 ml. of refluxing ethyl alcohol, followed immediately by one-half gram of 1-carboxymethylene-Z-methallyl-2, 4b dimethyl 7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,l0, l()a-dodecahydrophenanthrenel-one. The resulting mixture was stirred vigorously for aperiod of about fifteen minutes. The reaction mixture was evaporated to one half volume in vacuo, and the concentrated solution was diluted with water. The aqueous solution was extracted withchloroform, and this extract, after being dried, was evaporatedto dryness in vacuo. The residual crystalline material was fractionally crystallized from acetonitrile to give substantially pure 1-carboxymethyl-2-methallyl 2,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7, 8,l0,10a-dodecahydrophenanthrene-4-ol.

In accordance with the foregoing experimental procedure and utilizing as starting material the stereoisomer of l carboxymethylene-2-methallyl-2,4b dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a, dodecahydrophenanthrene-4-one having an M. P. of'203-205 C., there was obtained the stereoisomer of l-carboxymethyl-2-methallyl 2,4b dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7, 8,10, 10-dodecahydrophenanthrenei-ol having an M. P. of S-257 C.

' Example 6 Onepart of 1-carboxymethylene-Z-methallyl-2,4b-dimethyl 7 ethylenedioxy l,2,3,4,4a',4b,5,6,7,8,10,10adodecahydrophenanthrenel-one (M. P. 203-205 C.) was reacted. with about 2.4. parts of sodium metal utilizingthe same procedure as that described in Example 5 hcreinabove except that n-butanol was used for the reduction medium in place of ethyl alcohol. The reaction mixture was worked up as in Example 5 to give substantially pure 1-carboxymethyl-2-methallyl,2,4b-dimethyl 7' ethylenedioxy' l,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-ol (M. P. 255257 C.).

Example 7 A mixture of one part of l-carboxymethylene-2-methallyl 2,4b dimethyl 7 ethylenedioxy l,2,3,4,4a,-

4b, 5,6,7,8,l0,l0a dodecahydrophenanthrene 4 one (M. P. 203205 C.), about 4 parts of potassium metal, and-about 40 ml. of n-butanol was stirred at the reflux temperature of the solvent for a period of about fifteen Example 8 'A solution of 2.75 g. of 1-carboxymethyl-Z-methallyl- 2,4b dimethyl 7 dimethyl-7-ethylenedioxy 1,2,3,4,-

4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene 4 01 was treated with an excess of diazornethane in ether. After standing overnight at room temperature the solvents were removed by evaporation. Theresidual oil was crystallized from ether, and the crystalline material thus obtained recrystallized from a mixture of ethyl acetate, ether, and petroleum ether to give substantially pure 1 carbomethoxymethyl 2 methallyl 2,4b dimethylethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,1051 dodecaliydrophenanthrene-4ol.

in accordance with the foregoing experimental procedure and utilizing as starting material the stereoisomeroE l-carboxymethyl-2-methallyl-2,4b-dimethyl-7-ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10a, dodecahydrophenanthrene-4-ol having an M. P. of 226-228 C., there was obtained the stereoisomer of carbomethoxymethyl-2- methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,-

17 4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 01 having an M. P. of l3S-l39 C.

When the stereoisomer of l-carboxymethyl-Z-methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,- 4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 01 having an M. P. of 255-257 C. was used as starting material there was obtained the stereoisomer of 1-carbomethoxymethyl 2 methallyl 2,4b dimethyl 7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-401 having an M. P. of 157-158 C.

When the stereoisomer of l-carboxyrnethyl-Z-methally] 2,4b dimethyl 7 ethylenedioxy l,2,3,4,4a,- 4b,5,6,7,8,l0,10a dodecahydrophenanthrene 4 ol having an M. P. of 2l6-220 C. was used as starting material there was obtained the stereoisomer of l-carbomethoxymethyl 2 methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-ol having an M. P. of 83-85 C.

A solution containing about 50 mg. of l-carbomethoxymethyl 2 methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,. ,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-ol and about 15 mg. of p-toluene sulfonic acid in about 3 ml. of acetone was heated under reflux for a period of about twenty minutes. The acetone reaction mixture was diluted with water and the resulting aqueous mixture extracted with chloroform. The chloroform extract was dried and evaporated to dryness to give l-carbomethoxymethyl 2 methallyl 2,4b dimethyl 1,2,3,- 4,4,4b,5,6,7,9,10,10a dodecahydrophenanthrene 4- ol-7-one. When the stereoisomer of l-carbomethoxymethyl 2 methallyl 2,4b dimethyl 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,l0,la dodecahydrophenanthrene-4-ol having an M. P. of 137-138" C. was used as starting material, there was obtained the stereoisomer of 1-carbomethoxymethyl-2-methallyl-2,4b-dimethyl-l,2,- 3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene 4- ol7-one having an M. P. of 133-134" C.

Example 9 A suspension of 4.15 g. of l-carboxymethyl-Z-methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,- 6,7,8,1(),10a dodecahydrophenanthrene 4 01 and 8 g. of anhydrous potassium carbonate in 50 ml. of dry acetone containing 8 ml. of methyl iodide was stirred, in a loosely-stoppered flask, at room temperature for a period of about fifteen hours. The reaction solution was filtered thereby removing the precipitated potassium iodide and excess potassium carbonate. The acetone was evaporated from the filtered solution in vacuo, and the residual oil was dissolved in ether; the ethereal solution was washed twice with 10 ml.-portions of water, dried over anhydrous sodium sulfate, and the solvents evaporated. The residual oil was crystallized from ether and dried to give substantially pure l-carbomethoxymethyl 2 -'nethallyl 2,4b, dimethyl 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,1021 dodecahydrophenanthreue-4-ol.

In accordance with the foregoing experimental procedure and utilizing the stereoisomer of l-carboxymethyl- 2 methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,- 4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 01 having an M. P. of 216-220 C. as starting material, there was obtained the stereoisomer of l-carbomethoxymethyl 2 methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,1021 dodecahydrophenanthrene-4-ol having an M. P. of 83-85 C.

Example 10 A solution of 350 mg. of l-carbomethoxymethyl-Z- methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,- 4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 01 in 3.5 ml. of pyridine was added to the complex formed byadding 350 mg. of chromium trioxide to 3.5 ml. of pyridine. The resulting mixture was shaken, and allowed to stand at room temperature in a closed vessel for a period of about fifteen hours. The reaction mixture was diluted with about 30 ml. of water, and the aqueous-solution was extracted with three 50 ml.-portions of ether. The ethereal extracts were combined, washed twice with water, dried over anhydrous sodiumsulfate, and the solvent evaporated. The residual oil was crystallized twice from ether to give substantially pure 1-carbometh oxymethyl 2 methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one.

In accordance with the foregoing experimental procedure and utilizing as starting material the stereoisomer of 1 carbomethoxymethyl 2 methallyl 2,4b dimethyl 7 ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-o1 having an M. P. of 138- 139 0., there was obtained the stereoisomer of l-carbomethoxymethyl 2 methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a'- dodecahydrophenanthrene-4-one having an M. P. of -127 C.; when the stereoisomer of 1 carbomethoxymethy-l 2 methallyl 2,4b dimethyl 7 ethylenedioxy-1,2,3,4,4a,- 4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-o1 having an M. P. of 157-158 C. was used as starting material there was obtained the stereoisomer of l-carbomethoxymethyl 2 4 methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenan threne-4-one having an M. P. of 140-141 0.; when the stereoisomer of 1 carbomethoxymethyl 2 methallyl-v 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,- 8,10,10a-dodecahydrophenanthrene-4-ol having an M. P. of 83-85 C. was used as starting material there was ob-, tained the stereoisomer of l carbomethoxymethyl -2+ methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,- 4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 one having an M. P. of 142-146 C.

When the stereoisomer of 1-carboxymethyl-2-methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,- 6,7,8,10,10a dodecahydrophenanthrene 4 01 having an M. P. of 234-235 C. was reacted with diazomethane in ether in accordance with the procedure described in Example 8 hereinabove, and the resulting stereoisomer of 1 carbomethoxymethyl 2 methallyl 2,4b dimethyl- 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-ol reacted with chromium tnioxidepyridine complex in accordance with the procedure described in the present example there was obtained the stereoisomer of 1 carbomethoxymethyl 2 methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,- 8,10,10a dodecahydrophenanthrene 4 one having an M. P. of C.

Upon heating together, under reflux, 1 carbomethoxye methyl 2 methallyl 2,4b dimethyl 7 ethylene dioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 one and an acetone solution of p-toluene sulfonic acid, whereby the ethylenedioxy substituent is hydrolyzed without appreciably aifecting the carbomethoxy ester grouping, there is obtained 1 carbomethoxymethyl- 1,2,3,4,4a,4b,5,6,7,9,10,1021 dodecahydrophenanthrenee 4,7-dione.

Example 11 To a solution of 378 mg. of 1 carbomethoxymethyl 2 methallyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,- 4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 one in 3 ml. of dry ether and 0.5 ml. of dry benzene was add-ed 254 mg. of osmium tetroxide. The resulting solution began to deposit in a few minutes a brown-black precipitate which can be recovered by filtration and dried to give the osmate ester of l-carbomethoxy-methyl-Z- (beta, gamma-dihydroxyisobutyl) 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanth'rene-4-one. Instead of isolating the osmate ester, the reaction mixture was allowed to stand at room temperature for a period of one hour, and 18 ml. of ethanol was then added to the reaction mixture. A solution of 0.8 g. of anhydrous sodium sulfite in 9 ml. of water was added to the alcoholic reaction mixture, the resulting mixture was vigorously agitated for a period of about three minutes, and the precipitated osmium oxide removed by filtration. The filtered reaction solution was cautiously acidified with dilute acetic acid to a pH of about 6, and the mildly acid aqueous solution was evaporated under reduced pressure to an oil. Water was added to the oil, and the aqueous mixture was extracted With ether. The ether extract was washed with water, dried over anhydrous sodium sulfate, and the ether evaporated. The residual crystalline material was crystallized from ethyl acetate to give 1 carbomethoxymethyl 2 (beta, gamma dihydroxyisobutyl) 2,4b d1 methyl 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one.

In accordance with the foregoing experimental procedure and utilizing as starting material the stereoisorner of l carbomethoxymethyl 2 methallyl 2,4b dimethyl- 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one having an M. P. of 125-123" C. there was obtained the stereoisomer of l-carbomethoxymethyl 2 (beta,gamma-dihydroxyisobutyl) 2,4bdimethyl 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrenei-one having an M. P. of 172- 174 C.; when the stereois'omer of 1 carbomethoxymethyl 2 methallyl 2,4b dimethyl 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one having an M. P. of 140-141 C. was used as starting material, there was obtained the stereoisomer of 1 carbomethoxymethyl 2 (beta,gamma-dihydroxyis'obut'yl) 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,- 4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 one having an M. P. of 142-155" C.; when the stereoisom'er of l carbomethoxymethyl 2 methallyl 2,4b dimethyl 7 ethylenedioxy l,2,3,4,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene 4 one having an M. P. of 142-146" C. was used as starting material, there was obtained the stereoisomer of 1 carbomethoxymethyl 2- (beta,gamma-dihydroxyisobutyl) 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,102. dodecahydrophenanthrene=4-one having an M. P. of l43-147 C.

.Upon heating together, under reflux, l-carbomethoxymethyl 2 (beta,gamma-dihydroxyisobutyl) 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4fone and an acetone solution of ptoluene sulfonic acid, whereby the ethylenedioxy substituent is hydrolyzed without appreciably aifecting the carbornethoxy ester grouping, there is obtained 1 -carbomethoxymethyl 2 (beta,gamma-dihydroxyisobutyl) 2,4b dimethyll,2,3,4,4a,4b,5,6,7,9,l0,10a dodecahydrophenanthrenetJ-dione.

Example 12 To a solution of 400 mg. of l-carbomethoxymethyl-2- (beta, gamma-dihydroxyisobutyl)-2,4b-dimethyl 7-ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,l0,la dodecahydrophenanthrene-4-one in 4 ml. of ethanol was added 1 ml. of pyridine and a solution of 350 mg. of periodic acid in 2 ml. of water. The resulting mixture was allowed to stand for a period of about six minutes at the end of which time the exothermic reaction which occurred was substantially complete. The reaction mixture was diluted with 20 ml. of water, and the aqueous mixture extracted with ether. The ether extract was washed with 5 ml. of water, dried over sodium sulfate, filtered and the ether evaporated. The residual oil was crystallized from petroleum ether to give substantially pure l-carbomethoxymethyl 2 acetonyl-2,4b-dimethyl .7 ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenan'threne- 4-one.

In accordance with the foregoing experimental procedure and utilizing as starting material the stereoisomer of l-carbomethoxymethyl 2 (beta,gamma-dihydroxyisobutyl) 2,4b-dimethyl -7 -ethylenedioxy- 1,2,3,4,4a,5,6,

7,8,l0,10a-dodecahydrophenanthrene-4-one having an M. P. of l72-174 C., there was obtained the stereoisomer of l-carbomethoxymethyl 2 {acetonyl 2,4b,dimethyl-7- ethylenedioxy l,2,3,4,4a,4i5,5;6,7,8,l0,l0a-dodecahydrophenanthrene-4-one which crystallized from ether in a crystal form having an M. P. of l08l09 C. and which crystallized from ethyl acetate-petroleum ether in a crystal form having an M. P. of -95 C.; when the stereoisomer of' 1-carbomethoxymethyl-2-(beta,gamma-dihydroxyisobutyl)-2,4b-dimethyl 7 ethylenedioxy-l,2,3,4,- 4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene 4 one having an M. P. of l42l55 C. was used as starting material, there was obtained the stereoisorner of l-carbomethoxymethyl 2 acetonyl-2,4b-dimethyl-7ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one having an M. P. of 132-l34 C.; when the stereoisomer of l-carboxymethoxymethyl 2 (beta,gamma-dihydroxyisobutyl)-2,4b-dimethyl 7 ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrenc- 4-one having an M. P. of 143l47 C. was used as starting material, there was obtained the stereoisomer of l-carbomethoxymethyl 2 acetonyl-2,4b-dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrenet-one having an M. P. of 144 C.

Upon heating together, under reflux, l-carbomothoxymethyl 2 acetonyl-2,4b-dimethyl-7-ethylenedioxy-l,2,- 3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene 4- one and an acetone solution of p-toluene sulfonic acid, there is obtained 1-carbomethoxymethyhZ-acetonyl-ZAbdimethyl 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4,7-dione.

Example 13 One gram of l-carbomethoxymethyl-Z,4b-dimethyl-7- ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one was dissolved in ml. of methanol. The resulting solution was cooled to a temperature of about 80 C. and a stream of ozonized oxygen containing one equivalent of ozone was passed, over a twominute period, through the cold solution. The reaction mixture was warmed to a temperature of about 0 C., and 10 ml. of Water was added to the mixture followed by five grams of zinc and 5 ml. of acetic acid. The resulting mixture was stirred for a period of about thirty minutes. Water and solid sodium carbonate were then added, the mixture was filtered, and the solvents were evaporated from the filtered solution in vacuo while maintaining the temperature of the solution below about 20 C. The residual material was extracted with ether and ether solution chromatographed on acid washed alumina. Upon evaporation of the ether-petroleum ether eluate there was obtained l-carbomethoxymethyl-Z-acetonyl 2,4b-dimethyl 7 ethylenedioxy-l,2,3,4,4a,4b,5,- 6,7,8,10,l0a-dodecahydrophenanthrene-4-one.

In accordance with the foregoing experimental procedure and utilizing as starting material the stereoisomer of l-carbomethoxymethyl 2 methallyl-2,4b-dimethyl-7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrenel-one having an M. P. of l27 C., there was obtained the stereoisomer of l-caromethoxymethyl 2 acetonyl-2,4b-dimethyl-7-ethylendioxy-1,2,3,- 4,4a,4b,5,6,7,8,l0,10a-dodecahydrophenanthrene 4 one having an M. P. of 108-109 C. when crystallized from ether.

Example 14 A solution of 506 mg. of l-carbomethoxymethyl-Z- acetonyl 2,4b-dimethyl '7 ethylenedioxy-l,2,3,4,4a,4b,- 5,6,7,8,10,10a-dodecahydrophenanthrene 4 one in benzene was distilled at room temperature until the volume of the solution was about 10 ml. This procedure assured a dry solution. This dry solution was added to solid sodium methoxide. (The solid sodium methoxide was prepared by removing the excess methanol from 2.4 ml. of a 1 molar methanol solution of sodium methoxide by baking at C. for thirty minutes in vacuo). The mixture of the benzene solution of the hydrophenanthrene compound and the solid sodium methoxide was allowed to stand at room temperature for a period of about twenty minutes, at the end of which time a flocculent solid precipitated from the benzene solution. The resulting mixture was stirred at room temperature for a period of about fifteen hours. A mixture of cold water C.) and ether was added to the reaction product and the resulting mixture was vigorously agitated. The aqueous phase was quickly separated and immediately acidified with an excess of an aqueous solution of sodium dihydrogen phosphate. The acidified aqueous solution was extracted with chloroform, and the organic extract was dried over anhydrous sodium sulfate, filtered, and the chloroform evaporated. The residual crystalline material was recrystallized from ethyl acetate-ether, and from ethanol, to give A 3-ethylenedioxy-l1,16,20-triketo-pregnene.

In accordance with the foregoing experimental procedure and utilizing as starting material the stereoisomer of l carbomethoxymethyl 2 acetonyl 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7, 8,10,1021- dodecahydrophenanthrene-4-one having an P. of 132-13-'t C., there was obtained the stereoisomer of A -3-ethylenedioxy-l 1,16,20-triketo-pregnene having an M. P. of 154156 (3.; when the stereoisomer of l-carbomethoxymethyl 2 acetonyl 2,4b dimethyl 7- ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one having, when crystallized from ether, an M, P. of 108109 C., there was obtained the stereoisomer of A -3-ethylenedioxy-11,16,20-triketo-pregnene having an M. P. of 226229 C.; when the stereoisomer of l carbomethoxymethyl 2 acetonyl 2,4bdimethyl 7 ethylenedioxy l,2,3,4,4a,'4b,5,6,7,8,l0,10adodecahydrophenanthrene-4-one, having an M. P. of 144 C. was used as starting material, there was obtained the stereoisomer of A -3-ethylenedioxy-l1,16,20-triketopregnene having an M. P. of 213215 C.

Upon heating together, under reflux, A -3-ethylenedioxy-1.1,16,20-triketo-pregnene and an acetone solution of p-toluene sulfonic acid (substantially in accordance with the procedure described in Example 1 hereinabove), there was obtained A -3,ll,16,20-tetraketo-pregnene; when the stereoisomer of A -3-ethylenedioxy-l'l;l6,20- triketo-pregnene having an M. P. of 154-l56 C. is used as starting material in this procedure, there was obtained the stereoisomer of A -3,l1,l6,2O-tetraketo pregnene having an M. P. of l87-l-89 -C.

Example 15 To a solution of 295 mg. of A -3-ethylenedioxy-11,16, ZO-triketo-pregnene in 3.7 ml. of pyridine was added 370 mg. of p-toluenesulfonyl chloride. The resulting mixture was allowed to stand at room temperature for about twenty-two hours. At the end of this period 2.3 ml. of saturated aqueous sodium bicarbonate solution were added to the cooled reaction mixture, thereby neutralizing the pyridine hydrochloride formed by the reaction as well as the excess of p-toluenesul-fonyl chloride. The aqueous pyridine mixture was agitated at room temperature for a period of about fifteen minutes during which time a crystalline product precipitated. Benzene was added to the reaction mixture, the mixture was poured onto ice, and dilute aqueous hydrochloric acid was added until the mixture was just acid. The organic layer was rapidly separated, washed with water, and with aqueous sodium bicarbonate solution. The washed organic layer was dried over sodium sulfate, and evaporated to dryness in vacuo. The residual material was recrystallized from benzene-petroleum ether-ether and then chromatographed on acid-washed alumina. The material obtained from the 1:1 petroleum ether--ether eluate was recrystallized from benzene-ether to give substantially pure A -3-ethylenedioxy-16-p-toluenesulf0noxy-l 1,20- diketo-pregnadiene.

In accordance with the foregoing experimental cedure and utilizing :as starting material thestereoisomer of A -3-ethylenedioxy-11,16,20-triketo-pregnene having an M. P. of 154156 C., there was obtained the stereoe isomer of A -3-ethylened=ioxy16-p-toluenesulfonoxy- 11,20-diketo-pregnadiene having an M. P. of l 99-20l C.; when the stereoisomer of A -3-ethylenedioxy-l1,1 6,20-. triketo-pregnene having an M. P. of 226-229 C. was used as starting material, there was obtained the stereoisomer of A -3-ethylenedioxylop-toluenesulfonoxy- 11,20-diketo-pregnadiene having an M. P. of 1891=90 (3.; when the stereoisomer of A -3-ethy'lenedioxyd1,16,20- triketo-pregnene having an M. P. of 213415 C. was used as starting material, there was obtained the stereoisomer of 'A -3-ethylenedioxy-1 6-p-toluenesulfonoxy- 11,20-diketo-pregnadiene having an M. P. of 198200 0.

Upon heating together, under reflux, A -3-ethylenedioxy 16 p toluenesulfonoxy 11,20 diketo pregnadiene and an acetone solution of p-toluene sulfonic acid, there is obtained A -16-p-toluenesulfonoxy-. 3,11,2O-triketo-pregnadiene.

Example 16 To a solution of 52 mg. of A -3-ethylenedioxy-16- p-toluenesulfonoxy-l1,20-diketo-pregnadiene in 10 ml. of benzene was added 2 g. of palladium catalyst (5% Pd on BaCOs) and the mixture was shaken at room temperature in contact with hydrogen under a pressure of about forty pounds per square inc-h. After about two hours, an additional 0.8 g. of catalyst was added and, after four more hours, another 0.8 g. of catalyst was added to the hydrogenation mixture. The resulting mixture was shaken for an additional fifteen hour period at room temperature in contact with hydrogen at a pressure of forty pounds per square inch. The reaction mix ture was filtered thereby removing the catalyst and the benzene was evaporated from the filtered solution in vacuo. The residual material was treated with ether and the crystalline product thus obtained was recrystallized from ether-petroleum ether-ether to give substantially pure A -3-ethylenedioxy-11,20-diketo-pregnene.

In accordance with the foregoing experimental procedure and utilizing as starting material the stereoisomer of A 3 ethylenedioxy 1 6 p toluenesulfonoxy- 11,20-diketo-pregnadiene having an M. P. of l99201 C (which was prepared using the stereoisomer of A 3- ethylened-ioxy-l1,16,20-triketo-pregnene of M. P. 154- 156 C.) there was obtained the stereoisomer of M6- ethylenedioxy-11,20-diketo-pregnene having an M. P. of 181-1825 C.; when the stereoisomer of A -3-ethy1- ened'ioxy 16 p toluenesulfonoxy 11,20 diketo pregnadiene having an M. P. of 1'8 91 C. was used as starting material, there was obtainedwthe stereoisomer of A -3-ethylenedioxy-11,20-diketo-pregnene having an M. P. of 142-145 C.; when the stereoisomer of A5116 3 ethylenedioxy l6 p toluenesulfonoxy- 11,20-diketo-pregnadiene having an M. P. of 198-200 C. (prepared, in turn, from the stereoisomer of A -3-ethylenedioxy-l1,-16,20-triketo-pregnene of M. P. 213- 215 C.) there was obtained the stereoisomer of A -3-. ethylenedioxy-l1,20-pregnene, having an M. 'P. of 171- 172 C.

Each of the three stereoi-somers of A -3-ethylenedioxy- 11,20-diketo-pregnene, when prepared as described in the present example, are obtained in the form of racernates; i. e. dl-A -3-ethylenedioxy-1 1,20-diketo-pregnene of M. P. 181-182.5 C.; dl-A -3-ethylenedioxy-11,20- d'iketo-pregnene of M. P. 142-145 C.; and dl-A -3- ethylenedioxy-11,20-diketo-pregnene of M. P. "1 7 1- 172C.

Example 17 To a solution of 20 mg. of A5-3-ethylenedioxy-1L20- diketo-pregnene in 1 ml. of tetrahydrofuran was added 0.5 ml. of 3 N aqueous perchloric solution. The reaction mixture was allowed toflstand at room temperature for a 23 period of approximately three and one-half hours. The solvents were evaporated from the reaction mixture in vaciio, and the residual material was extracted with chloroform. The chloroform extract was dried over sodium sulfate, and the solvent evaporated from the dry chloroform extract in vacuo. The residual material was recrystallized from ether to give A -3,l1,20-triketo-pregnene.

In accordance with the foregoing experimental procedureand utilizing the racernate of A -3-ethylenedioxyll,20-diketo-pregnene having an M. P. of 181-1825 C. as starting material, there was obtained the racemate of A -3,1LZO-diketQ-pregnene having an M. P. of 175.5- l76.5 0.; when the racemate of A -3-ethylenedioxy- 11,20-diketo-pr'egnene having an M. P. of 142-145 C. was used as starting material, there was obtained the racemate of A 311,20-triketo-pregnene having an M. P. of 153-158 C.; when the racemate of M-3-ethylenedioxy- 11,20-diketo-pregnene having an M. P. of 171-172 C. was used as starting material, there was obtained the racemate of A -3,1l,20-triketo-pregnene having an M. P. of 153 C. and 168 C. (dimorphic).

The racemate of A -3,11,20-tril1eto-pregnene having an M. P. of 1755-1765 C. possesses the stereoisomeric configuration characteristic of the naturally occurring steriod hormones such as progesterone; we refer to this racemate (M. P. 175.5-1765 C.) as dl-ll-keto-progesterone.

The 1-ethoxyethinyl-2-methallyl-2,4b-dimethyl-7- ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-l-ol-4-one used as starting material in Example 1 hereinabove can be prepared from 7-keto-4b-methy1- 1,2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene- 1,4-diol (the preparation of which is described in a copending application of applicants assignee Serial No. 228,126, filed May 24, 1951, and now issued as Patent No. 2,617,828 on November 11, 1952), in accordance with the following procedure:

Into a 5 liter flask equipped with a stirrer, a 1 liter dropping funnel and a sidearm with condensor attached in distilling position, were placed 38.9 g. (0.155 mole) of 4b methyl-l,2,3,4,4a,5,6,7,9,10,10a-dodecahydrophenanthrone-1,4-diol-7-one. 40 cc. (0.645 mole) of glycol, 2,500 cc. of ethylene dichloride and 0.4 g. (0.002'mole) of p-toluene sulfonic acid. This mixture was set stirring. Enough heat was applied to distill off 3 liters of the azeotrope of the solvent and water, formed as a byproduct, during a 3-hour period. During this time an additional 1,500 cc. of ethylene dichloride was added to keep the reactants in solution. After 3 hours the reaction mixture was cooled and thoroughly shaken with 50 cc. of an aqueous 1 normal potassium bicarbonate solution. The aqueous carbonate layer was drawn ofi and twice extracted with ethylene dichloride. All three ethylene dichloride extracts were then combined, dried over anhydrous magnesium sulfate and concentrated. This concentrate was taken up in 1 liter of acetone and concentrated until crystals just began to come out. Filtration of the cold acetone gives the crude crystalline product 4bmethyl 7 ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-1,4-diol which can be further purified by recrystallization from acetone. The pure product melts at 189 C.

Eighty-six and five tenths grams (0.294 mole) of 4bmethyl 7 ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-1,4-diol was dissolved in 2,130 g. (2,250 cc.) (21.7 moles) of cyclohexanone, and 2,250 cc. of benzene. To this solution was added 86.5 g. (0.424 mole) of aluminum isopropoxide, and the whole was then set to reflux for 12 hours. At the end of this time 25 cc. of water was added. The coagulated aluminum hydroxide thus formed was'filtered off. The filtrate was concentrated and dried in vacuo, leaving a residue which, on trituration with petroleum ether, gave the crude crystalline product 4b-methyl-7-ethylenedioxy-1,2,3,4,4a, 4b-,5,6,7,8,10,10a, dodecahydrophenanthrene-4-ol-1-one.

24 It can be purified by recrystallization from acetone and melts at 219-220" C.

To 10.0 g. of 4b-methyl-7-ethylenedioxy-l,2,3,4,4a,4b, 5,6,7,8,10,l0a-dodecahydrophenanthrene 4ol-1-one dissolved in ml. of benzene and 70 ml. of t-butyl alcohol was added, at reflux temperature, 1.5 equivalents of l M potassium t-butoxide in t-butyl alcohol, and 20 ml. of a 1:1 solution of methyl iodide in benzene. After 30 minutes of refluxing, the solution was quenched with water, concentrated in vacuo, and the concentrate extracted with CI-lCls. The CHCla extract was dried and the solvent removed in vacuo. Fractional crystallization of the crystalline residue from ethyl acetate, yielded the desired product, 2,4b dimethyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8, 10,10a-dodecahydrophenanthrene-4-ol-l-one, M. P. 189- 192" C.

A solution of 3.12 g. of 2,4b-dimethyl-7-ethylenedioxyl,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene 1- one-4-ol (M. P. 189-192 C.) in 30 cc. of pyridine was combined with 3.1 g. of chromium trioxide in 30 cc. of pyridine. The reaction flask was stoppered, the contents mixed thoroughly and allowed to stand at room temperatureovernight. The reaction mixture was poured into water and extracted with three portions of benzene-ether (1:1) with filtration through diatomaceous earth to break the emulsions. After washing with water, the combined organic solution was dried over anhydrous magnesium sulfate and concentrated with final drying of the residue under vacuum. Crystallization from ether gave crystalline 2,4b-dimethyl-7-ethylenedioxyl,2,3,4,4a,4b,5, 6,7,8,10,10a dodecahydrophenanthrene-1,4-dione M. P. -145 C. Chromatography over alumina and elution with petroleum ether-ether (8:2) gave two purified isomers, M. P. 136 C. and 152-153 C.

A solution of 16.0 g. of crude 2,4b-dimethyl-7-ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,10,loa-dodecahydrophenanthrene-l,4-dione (M. P. 130-145 C. and consisting of a mixture of isomers M. P. 135-136 C. and 152l53 C.) in 190 cc. of benzene was concentrated to 160 cc. to insure dryness. The solution was then placed under nitrogen, and treated successively with 16.0 cc. of methallyl iodide and 70 cc. of tertiary butyl alcohol containing 2.31 g. of dissolved potassium. After standing at room temperature for three hours, the mixture was poured into ether, the ethereal solution washed with water, concentrated to dryness and purified by chromatography on either acid washed or alkaline alumina, the product being eluted with petroleum ether-ether mixtures. Pure 2,4b-dimethyl- 2 methallyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-l,4-dione was obtained, M. P. l08l09 C.

Another isomeric form of this compound having a melting point of 138-139 C. was also recovered from the chromatographic column.

A solution of ethyl magnesium bromide (0.1526 m.) was prepared in the usual manner from 3.7 g. of magnesium. and excess ethyl bromide in 100 ml. of dry ether. A solution of 11.74 g. of ethoxyacetylene (0.165 m.) diluted with dry ether to a total volume of 4-0 ml. was added gradually to the ethyl Grignard and stirred until the evolution of ethane ceased. 120 ml. of dry benzene was added to dissolve the ethoxyacetylene magnesium bromide.

A solution of 27 g. of dry 2,4bdimethyl-2-methallyl- 7-ethylenedioxyl ,2,3,4,4-a,4b,5 ,6,7,8, 10, l (la-dodecahydrophenanthrene-lA-dione (stercoisomer of M. P. 108-109 C.) in m1. of dry benzene was added rapidly to the stirred Grignard solution. After standing at room temperature for two hours, the reaction mixture was decomposed by pouring into ice-water. Enough saturated aqueous ammonium chloride was added to break the emulsion which formed. The benzene-ether layer was separated and Washed once with water. The aqueous layer was extracted again with 500 ml. of a 1:1 benzene-ether solution which, after one water wash, was combined with the original extract. After drying over anhydrous sodium sulfate and removal of the latter by filtration, the solvents were distilled in vacuo. From a solution of the residual oil in ether were obtained crystals of the stereoisomer of l-ethoxyethinyl-2,4b-dimethyl-Z-methallyl- 7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-1-o1-4-one having an M. P. of 133134 C.

By using a stereochemical modification of the above starting material, M. P. 138139 C., and treating as above described, there was obtained the stereochemical modification of 1-ethoxyethiny1-2,4b-dimethyl-2-methallyl- 7-ethylenedioXy-1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydro phenanthrene-1-ol-4-one having an M. P. of 131-132 C.

Various changes and modification may be made in carrying out the present invention. Insofar as these 26 changes and modifications are within the purview of the annexed claims they are to be considered as part of our invention.

We claim:

1. The process which comprises reacting l-carboalkoxymethyl 2 acetonyl 2,4b dimethyl 4 4 keto 1,2,3,4, 4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene 7-ketal with a strong alkali under anhydrous conditions to produce A -11,16,20-triketo-pregnene 3-ketal, and reacting the latter compound with a hydrolyzing agent to form A -3 ,1 1,16,20-tetraketo-pregnene.

2. A -3,11,16,20-tetraket0-pregnene.

No references cited. 

1. THE PROCESS WHICH COMPRISES REACTAING 1-CARBOALKOXYMETHY -2- ACETONYL -2,4B - DIMETHYL -4- KETO -1,2,3,4, 4A,4B,5,6,7,8,10,10A-DODECAHYDROPHENANTHRENE 7- KETAL WITH A STRONG ALKALI UNDER ANHYDROUS CONDITIONS TO PRODUCE $5-11,16,20-TRIKETO-PREGNENE 3-KETAL, AND REACTING THE LATTER COMPOUND WITH A HYDROLYZING AGENT TO FORM $4-3,11,16,20-TEKRAKETO-PREGNENE. 